Human positron emission tomographic (PET) scanning, using the [18F]fluoro-deoxyglucose (FDG) method in placebo-controlled crossover studies, showed that euphorigenic doses of morphine or cocaine decrease rCMRglc, especially in cortical regions. The findings suggest that drugs of abuse produce euphoria by a mechanism which involves a reduction of rCMRglc. This hypothesis is being tested by examining the effects of other abused drugs (nicotine, buprenorphine). Future PET studies with FDG will be used to obtain an objective measure of the opioid abstinence syndrome in human subjects, in order to test the effects of potential medications. Effects of nicotine and psychomotor stimulants on rCMRglc were studied by the deoxyglucose (DG) method in rats. Whereas nicotine stimulated rCMRglc in a pattern reflecting the distribution of nicotinic receptors, chronic nicotine produced tolerance, seen as a reduced response in some areas. In Fischer-344 rats, cocaine increased rCMRglc in motor areas and reduced rCMRglc in the lateral habenula. Lewis rats were more sensitive to the effects than Fischer-344 rats, and showed reductions in rCMRglc of the cortex, suggesting that genetic differences may influence susceptibility to cocaine abuse. Studies in gallamine-treated rats demonstrated that effects of psychomotor stimulant drugs on rCMRglc in motor systems are not secondary to limb movement. The DG method also was used to identify brain areas important to opioid analgesia and the opioid abstinence syndrome. Although the formalin pain model was not associated with significant differences in rCMRglc as compared with control, morphine produced a dose-dependent reduction of rCMRglc in thalamic nuclei as well as in other areas implicated in nociception. The DG method was used to show that hypermetabolism in the brain, precipitated by administration of naloxone to opioid-dependent rats, is reversed by doses of clonidine which attenuate the opioid abstinence syndrome. Thus, efficacy of therapeutic interventions may be monitored by in vivo brain imaging in humans, using PET.